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Memantine
Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system. Memantine was developed by Merz and licensed to Forest for the U.S. and Lundbeck for selected European and international markets. Memantine is marketed under the brands Axura® and Akatinol® by Merz, Namenda® by Forest and Ebixa® by Lundbeck. Pharmacology Glutamatergic (NMDA receptor) A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is involved in the aetiology of Alzheimer's disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system.Cacabelos R, Takeda M, Winblad B. The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease. Int J Geriatr Psychiatry 1999;14(1):3-47. PMID 10029935 Memantine is a moderate-affinity voltage-dependent noncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions which forms the basis of neuronal excitotoxicity. The low-affinity of memantine, however, preserves the physiological function of the receptor as it can still be activated by the relatively high concentrations of glutamate released following depolarisation of the presynaptic neuron. Serotonergic (5-HT3 receptor) Memantine acts as an uncompetitive antagonist at the 5HT3 receptor, with a potency similar to that for the NMDA receptor.Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG. The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 2001;306(1-2):81-4. PMID 11403963 The clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown. Cholinergic (Nicotinic acetylcholine receptor) Memantine acts as an uncompetetive antagonist at different neuronal nicotinic neuronal receptors (nAChRs) at potencies similar to the NMDA receptor.Buisson B, Bertrand D. Open-channel blockers at the human α4β2 neuronal nicotinic acetylcholine receptor. Mol Pharmacol 1998;53:555–63. PMID 9495824Aracava Y, Pereira EF, Maelicke A, Albuquerque EX. Memantine blocks α7* nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther 2005;312:1195–205. PMID 15522999 It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists are viewed as interesting targets for anti-Alzheimer drugs.Gotti C, Clementi F. Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 2004;74:363–96. PMID 15649582 Clinical use Indications Although Memantine is approved for treatment of moderate to severe Alzheimer's DiseaseMount C, Downton C. Alzheimer's Disease: Progress or Profit?. Nature Medicine 2006 (12) 3: 1280-1284. PMID 16829947 its usage has been recommended against by the UK's National Institute for Clinical Excellence. NICE technology appraisal guidance 111 Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer’s disease Memantine has been associated with a moderate decrease in clinical deterioration in Alzheimer's disease. A systematic review of randomised controlled trials found that memantine has a small positive effect on cognition, mood, behaviour, and the ability to perform daily activities in moderate to severe Alzheimer's disease, but an unknown effect in mild to moderate disease.Areosa SA, Sherriff F, McShane R. Memantine for dementia. Cochrane Database Syst Rev 2005;(3):CD003154. PMID 16034889 Memantine is also being tested for Systemic Lupus Erythematosus, depression, obsessive compulsive disorder, glaucoma, tinnitus, neuropathic pain, and pervasive developmental disorders. Adverse drug reactions Memantine is generally well-tolerated. Common adverse drug reactions (≥1% of patients) include: confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include: vomiting, anxiety, hypertonia, cystitis, and increased libido.Joint Formulary Committee. British National Formulary. 47th ed. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain; 2004. ISBN 0-85369-584-9Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. See also *Alzheimer's disease *Donepezil *Galantamine *Rivastigmine *Exelon References External links * Pubmed abstract: The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders :de:Memantin :tr:Memantin Category:Antidementia agents Category:NMDA receptor antagonists